Activations of muscarinic M₁ receptors in the anterior cingulate cortex contribute to the antinociceptive effect via GABAergic transmission

Abstract

BackgroundCholinergic systems regulate the synaptic transmission resulting in the contribution of the nociceptive behaviors. Anterior cingulate cortex is a key cortical area to play roles in nociception and chronic pain. However, the effect of the activation of cholinergic system for nociception is still unknown in the cortical area. Here, we tested whether the activation of cholinergic receptors can regulate nociceptive behaviors in adult rat anterior cingulate cortex by integrative methods including behavior, immunohistochemical, and electrophysiological methods.ResultsWe found that muscarinic M1 receptors were clearly expressed in the anterior cingulate cortex. Using behavioral tests, we identified that microinjection of a selective muscarinic M1 receptors agonist McN-A-343 into the anterior cingulate cortex dose dependently increased the mechanical threshold. In contrast, the local injection of McN-A-343 into the anterior cingulate cortex showed normal motor function. The microinjection of a selective M1 receptors antagonist pirenzepine blocked the McN-A-343-induced antinociceptive effect. Pirenzepine alone into the anterior cingulate cortex decreased the mechanical thresholds. The local injection of the GABAA receptors antagonist bicuculline into the anterior cingulate cortex also inhibited the McN-A-343-induced antinociceptive effect and decreased the mechanical threshold. Finally, we further tested whether the activation of M1 receptors could regulate GABAergic transmission using whole-cell patch-clamp recordings. The activation of M1 receptors enhanced the frequency of spontaneous and miniature inhibitory postsynaptic currents as well as the amplitude of spontaneous inhibitory postsynaptic currents in the anterior cingulate cortex.ConclusionsThese results suggest that the activation of muscarinic M1 receptors in part increased the mechanical threshold by increasing GABAergic transmitter release and facilitating GABAergic transmission in the anterior cingulate cortex.

Cholinergic modulation inhibits cortical spreading depression in mouse neocortex through activation of muscarinic receptors and decreased excitatory/inhibitory drive

“…Inhibitory muscarinic actions that could be consistent with CSD inhibition and decreased excitatory/inhibitory ratio have been reported. For example, in vivo microinjections in the rat anterior cingulate cortex of McN-A-343 (the same preferential M1 agonist that we have used) induced increased GABAergic synaptic transmission and anti-nociceptive effects to mechanical stimuli (Koga et al, 2017). Moreover, muscarinic actions have been implicated in long term depression (LTD) of synaptic functions.…”

Chronic inflammatory pain induced GABAergic synaptic plasticity in the adult mouse anterior cingulate cortex

“…For analyzing GABA A receptor-mediated tonic currents, bicuculline methiodide (10 μM) was applied in the bath solution. 19 , 21 , 22 Bipolar stimulating electrodes were placed in layer V/VI of the ACC slices to detect evoked IPSCs (eIPSCs). 12 , 20 , 23 , 24 The eIPSCs were induced by repetitive stimulations every 30 s, and recorded neurons were voltage clamped at 0 mV.…”

“… 17 In animal studies, GABAergic synaptic transmission enhancement, by a muscarinic receptor agonist injected into the ACC, produces antinociceptive behaviors. 19 Although a chronic inflammatory pain model (in one to three days) obviously enhanced glutamatergic transmission in the superficial layers of the ACC, 13 , 15 whether the early stage of a major chronic inflammatory pain model could produce GABAergic synaptic plasticity is not fully understood in layer II/III of the ACC.…”

Molecular, Cellular and Circuit Basis of Cholinergic Modulation of Pain

“…Pharmacological M 1 -mAchR stimulation in the rat ACC was recently shown to exert an analgesic effect in naïve animals by virtue of increasing the frequency and amplitude of GABA A -mediated IPSCs ( Koga et al, 2017 ). Mechanistically, it remains unclear whether M 1 -mediated postsynaptic modulation, which has been reported in addition to presynaptic regulation of GABA release from inhibitory interneurons ( Domínguez et al, 2014 , Koga et al, 2017 ), also plays a role in pain modulation.…”